Development and Validation of a Prognostic Signature Based on Transcription Factors Associated with Endoplasmic Reticulum Stress in Pancreatic Adenocarcinoma

Endoplasmic reticulum stress (ER stress) plays a crucial role in influencing the malignant behaviors of various tumors. Targeting the expression or degradation of transcription factors (TFs) offers a promising avenue for cancer treatment. However, a detailed understanding of how ER stress affects TF function and their interactions remains limited. This study aims to develop a prognostic model and identify TFs associated with ER stress in pancreatic ductal adenocarcinoma (PDAC).

We obtained gene expression profiles and corresponding clinical data from The Cancer Genome Atlas (TCGA). To develop a prognostic signature, we performed several analyses, including unsupervised clustering, enrichment analysis, immune infiltration assessment, as well as univariate, LASSO, and multivariate Cox regression analyses. Four transcription factors—STAT1, IRF6, NRF1, and RXRA—were incorporated into a risk model, which was subsequently validated using the GSE dataset. Additionally, we examined IRF6 through quantitative PCR, western blotting, flow cytometry, and immunohistochemistry in vitro using pancreatic cancer cell lines and a tissue microarray.

The high-risk group identified by the model exhibited significant associations with immune cell infiltration and poorer survival outcomes, though there was no significant correlation with tumor purity (p = 0.19). Furthermore, IRF6 downregulation in vitro was found to inhibit pancreatic cancer cell proliferation and promote apoptosis. IRF6 depletion also increased the expression of key molecules involved in ER stress at both the transcriptional and translational levels. Immunohistochemical analysis revealed marked differences in IRF6 expression between tumor and adjacent non-tumor tissues (59.29±29.88 vs. 95.22±40.80, p<0.001).

This study provides evidence that the constructed risk model can effectively predict prognosis in PDAC patients. Transcription factors related to ER stress, such as IRF6, show promise as both prognostic biomarkers and potential therapeutic targets for PDAC.